Through the development of mouse models of coxsackievirus B3 (CB3)-induced and cardiac myosin-induced autoimmune myocarditis, we have shown that modulation of cytokines, IL-1, TNF-alpha and IFN-gamma affects the severity of both virus and myosin-induced myocarditis. The role of these cytokines and in addition, the role of IL-6, IL-10 and TGF-beta on the mechanisms linking inflammatory heart disease with impaired cardiac function and induction of cardiac autoimmunity will be explored. We hypothesize that, (1) pro-inflammatory (Il-1, TNF-alpha, IFN-gamma) and regulatory (IL-6, IL-10, TGF-beta) cytokines which are produced in locally inflamed hearts promote the induction of cardiac autoimmunity and/or increase the vulnerability of the heart to damage. We will establish the presence of and kinetics of cytokine production in CB3- and myosin-induced disease. (2) Blocking cytokine biological activity, specifically IL-1 and TNF-alpha through the use of IL-1 receptor antagonist (IL-1ra) and TNF soluble receptor (TNFsR), respectively will modify the expression of viral and autoimmune phases of the disease. And, (3) local cytokine production may in part exert its effects through the production of nitric oxide, which may directly or indirectly orchestrate cardiac myocyte dysfunction or contribute to myocyte damage. In vivo studies on the role of nitric oxide (NO) and the effects of nitric oxide synthase inhibitors on the development of postinfectious autoimmune disease will be examined. Human myocarditis is a significant cause of severe, but potentially reversible, cardiac dysfunction which may serve as a paradigm of inflammatory heart disease. The mechanisms leading to cardiac dysfunction and failure are unknown. Enteroviruses are among the most common etiologic agents of human myocarditis and a significant proportion of patients progress to late stage idiopathic dilative cardiomyopathy (IDC) and have autoantibodies to a number of cardiac antigens. There is considerable evidence for cytokine-mediated modulation of cellular physiology and immune processes involving inflammatory disease. Identifying a role for specific cytokines in myocardial pathology would provide an opportunity for development of molecular interventions for the treatment of morphological and functional abnormalities associated with myocarditis and IDC.